Precision DNA demethylation ameliorates disease in lupus-prone mice

作者：Hao Li, Maria Tsokos, Sean Bickerton, Amir Sharabi, Yi Li, Vaishali R. Moulton, Philip Kong, Tarek M. Fahmy, George C. Tsokos · 发表于：JCI Insight · 年份：2018 · DOI：10.1172/jci.insight.120880 · 被引用次数：54 · 研究领域：Immune Cell Function and Interaction、T-cell and B-cell Immunology、Immune cells in cancer

Defective DNA methylation in T cells leads to a series of T cell abnormalities in lupus; however, the full effect of T cell lineage-specific DNA methylation on disease expression has not been explored. Here, we show that 5-azacytidine, a DNA methyltransferase inhibitor, targeted to either CD4 or CD8 T cells in mice with established disease using a nanolipogel delivery system dramatically ameliorates lupus-related pathology through distinct mechanisms. In vivo targeted delivery of 5-azacytidine into CD4 T cells favors the expansion and function of Foxp3+ Tregs, whereas targeted delivery to CD8 T cells enhances the cytotoxicity and restrains the expansion of pathogenic TCR-αβ+CD4-CD8- double-negative T cells. Our results signify the importance of cell-specific inhibition of DNA methylation in the treatment of established lupus.